Briefly, according to the present invention, there are provided selective modulators of nicotinic acetylcholine receptors. More particularly, the present invention provides pyridyl ethers and thioethers as selective nicotinic acetylcholine receptor agonists, partial agonists, antagonists or allosteric binding molecules useful in the treatment of pain, Alzheimer""s disease, memory loss or dementia or loss of motor function.
Holladay, et. al., in xe2x80x9cIdentification and Initial Structure-Activity Relationship of (R)-5-(2-Azetidinylmethoxy)-2-chloropyridine (ABT594), a Potent, Orally Active, Non-Opiate Analgesic Agent Acting via Neuronal Nicotinic Acetylcholine Receptorsxe2x80x9d, 1998, J. Med. Chem., 41, 407, describe the preparation of ABT594 and its therapeutic utility. A similar disclosure is made by Donnelly-Roberts, et. al., 1998, J. Pharmacol. Exp. Ther., 285, 777 and 787; Decker, et. al., 1998, Eur. J. Pharmacol., 346, 23 and in WO 98/25920; wherein ABT594 is contained within the general structure: 
Abreo, et. al., in xe2x80x9cHeterocyclic Ether Compounds that enhance Cognitive Functionxe2x80x9d, 1994, W.O. Patent 94/08992, describes the preparation of heterocyclic ether compounds and itstherapeutic utility. A similar disclosure is made in Abreo, et. al., 1996, J. Med. Chem. 39, 817. Generally, the heterocyclic ether compounds have the structure: 
where A is saturated heterocycle, B is unsaturated heterocycle and R is H or C1-6alkyl.
Lin, et. al., in xe2x80x9c3-Pyridyloxymethyl Heterocyclic ether Compounds useful in Controlling Chemical Synaptic Transmissionxe2x80x9d, 1997, U.S. Pat. No. 5,629,325, describe the preparation of pyridyl ether compound and its therapeutic utility. A similar disclosure is made by Lin, et. al., 1997, J. Med. Chem. 40, 385. Generally, the 3-Pyridyloxymethyl heterocyclic ether compounds have the structure: 
wherein R1 is H or C1-6alkyl; R2 is H, F, Cl, vinyl or phenyl; L is a C1-6 linking group and R3 is H or C1-6alkyl.
Shanklin, et. al., in xe2x80x9cAryloxy and Aryloxyalklazetidines as Antiarrhythmic and Anticonvulsant Agentsxe2x80x9d, 1992, U.S. Pat. No. 5,130,309, describe the preparation of Aryloxy and aryloxyalkyllazetidines and their therapeutic utilities. Generally, the described azetidines have the formula: 
wherein n is 0 to 3, R is H, C1-4alkyl or arylalkyl and Ar is phenyl or substituted phenyl.
Cosford, et. al., in xe2x80x9cSubstituted Pyridine Derivatives, Their Preparation and Their Use as Modulators of Acetylcholine Receptorsxe2x80x9d, 1996, W.O. Patent 96/31475, describe the preparation of substituted pyridine derivatives and its therapeutic utility. Generally, the pyridine derivative have the formula: 
wherein A is 1-6 atoms bridging species linking pyridine and N, B is 1-4 atoms bridging species linking N and Z, Z is H, C1-6alkyl, alkynyl or aryl; R3 is H or lower alkyl; and R2, R4, R5, and R6 are H, C1-6alkyl, alkynyl, aryl or S-containing groups.
McDonald, et. al., in xe2x80x9cModulators of Acetylcholine Receptorsxe2x80x9d. 1998, U.S. Pat. No. 5,723,477, describe the preparation of C-3 substituted pyridyl compounds and its therapeutic utility. A similar disclosure is made in McDonald, et. al., 1997, U.S. Pat. No. 5,703,100; McDonald, et. al., 1997, U.S. Pat. No. 5,677,459; Menzaghi, et. al., 1997, J. Pharmacol Exp. Ther. 280, 373, 384, and 393; and Lloyd, et. al., 1998, Life Sci., 62, 1601. Generally, the C-3 substituted pyridyl compounds have the formula: 
wherein A is 1-3 atom bridging moiety, forming a 5-7 membered ring; B is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94CHR10xe2x80x94, xe2x95x90CR10xe2x80x94 or xe2x95x90Nxe2x80x94; R2, R4, R5 and R6 are H, C1-6alkyl, aryl, alkynyl, or O-, S-, or N(R)-containing group; and R7 and R9 are H, C1-6alkyl, aryl, or alkynyl.
Caldwell, et. al., in xe2x80x9cMethod for Treatment of Neurodegenerative Diseasesxe2x80x9d 1993, U.S. Pat. No. 5,212,188, describe the preparation of alkenyl pyridyl compounds and its therapeutic utility. A similar disclosure is made in Bencherif, et. al., 1996 J. Pharmacol. Exp. Ther., 279, 1413 and 1422. Generally, the alkenyl pyridyl compounds have the general formula: 
wherein n is 1-5, R is H or C1-5alkyl and X is halogen.
Crooks, et. al., in xe2x80x9cNicotinic Receptor Antagonists in the Treatment of Neuropharmacological Disordersxe2x80x9d 1997, U.S. Pat. No. 5,691,365, describe the preparation of nicotine analogs and its therapeutic utility. Generally, the nicotinic analogues have the structure: 
wherein R is alkyl or branched alkyl with 2-19 carbon atoms, cycloalkyl, aralkyl or alkenyl.
Shen, et. al., in xe2x80x9c7-Azabicyclo[2.2.2]-Heptane and -Heptene Derivatives as Cholinergic Receptor Ligandsxe2x80x9d 1996, W.O. Patent 96/06093, describe the preparation of 7-azabicyclo[2.2.2]-heptane and -heptene derivatives and their therapeutic utilities. A similar disclosure is made by Shen, et. al., 1994, W.O. Patent 94/22868. Generally, the heptane and heptene derivatives have the formula: 
wherein R1, R2, R3, R4, R5, R6, and R7 are H, alkyl or an alkyl-heteroatom containing group.
Dybes, et. al., in xe2x80x9cAnticoccidal Cyclicaminoethanols and Esters Thereofxe2x80x9d 1978, U.S. Pat. No. 4,094,976, describe the preparation of cyclicaminoethanols and esters and their therapeutic utilities. Generally, the cyclicaminoethanols have the formula: 
wherein n is 3-5 and R is H or acyl radical.
Caldwell, et. al., in xe2x80x9cMethod for Treatment of Neurodegenerative Diseasexe2x80x9d 1993, U.S. Pat. No. 5,214,060 describes the preparation of 3-aminoalkylpyridines and its therapeutic utilities. Generally, the 3-aminoalkylpyrimidines have the formula: 
wherein R is C1-7alkyl, X is substituent other than H, p is 1-5, m is 0-4 and n is 0-8.
There are two recent reviews on the topic of the nicotinic acetylcholine receptor: Holladay, et. al., in xe2x80x9cNeuronal Nicotinic Acetylcholine Receptors as Targets for Drug Discoveryxe2x80x9d 1997, J. Med. Chem., 40, 4169; and Holladay, et. al., in xe2x80x9cStructure-Activity Relationships of Nicotinic Acetylcholine Receptor Agonists as Potential Treatments for Dementiaxe2x80x9d 1995, Drug Dev. Res., 35, 191.
There are provided by the present invention selective modulators of the nicotinic acetylcholine receptor of the general formula: 
wherein
m is selected from 0, 1 or 2;
p is selected from 0 or 1;
Y is selected from the group consisting of O, S, S(O) and S(O)2;
R1 is independently selected from the group consisting of Hxe2x80x94, HOxe2x80x94, Oxe2x80x94, C1-6alkyl-, C2-6alkenyl-, C2-6alkynyl-, C3-6cycloalkylC1-3alkyl-, phenylC1-3alkyl-, xe2x80x94C(O)C1-6alkyl, xe2x80x94C(O)phenyl, xe2x80x94C(O)C1-6alkylphenyl, xe2x80x94C(O)OC1-6alkyl, xe2x80x94C(O)Ophenyl, xe2x80x94C(O)NHC1-6alkyl, xe2x80x94C(O)N(C1-6alkyl)2 and xe2x80x94C(O)NHphenyl; wherein R1 is optionally substituted on a carbon atom with one to three Ra substituents; wherein Ra is independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxyC1-4alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F;
R2 is independently selected from the group consisting of H, C1-6alkyl, phenyl and heteroaryl; wherein heteroaryl is as defined below;
R3 is selected from the group consisting of H, C1-6alkyl, Cl, Br and F; with the proviso that if m is 0, then R3 is not Cl, Br or F; and
R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen and selected radicals; wherein the radicals are selected from the group consisting of:
a) a trifluoromethyl group: xe2x80x94CF3;
b) a halogen atom: xe2x80x94Br, xe2x80x94Cl, xe2x80x94F or xe2x80x94I;
c) a C1-4alkoxy radical: xe2x80x94OC1-4alkyl; wherein the alkyl is optionally mono- or di-substituted by Rq; wherein
Rq is selected from the group consisting of xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94C(O)NH2, xe2x80x94OCxe2x80x94(O)NH2, CHO, xe2x80x94OC(O)N(CH3)2, xe2x80x94SO2NH2, SO2N(CH3)2, xe2x80x94SOCH3, SO2CH3, xe2x80x94F, xe2x80x94CF3, xe2x80x94COOMa (wherein Ma is selected from the group consisting of hydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by Ma, as defined previously) and xe2x80x94SO3Mb (wherein Mb is selected from the group consisting of hydrogen and an alkali metal);
d) a hydroxy group: xe2x80x94OH;
e) a carbonyloxy radical: xe2x80x94O(Cxe2x95x90O)Rs; wherein
Rs is a group selected from the group consisting of C1-4alkyl, phenyl and heteroaryl (each of which is optionally mono- or di-substituted with Rq, as defined previously); wherein
heteroaryl is a monocyclic aromatic hydrocarbon group having five or six ring atoms, having at least one carbon atom which is the point of attachment, having from one to three carbon atoms replaced by N in the case of six ring atoms, having one carbon atom replaced by O, S or N in the case of five ring atoms and, optionally, having up to three additional carbon atoms replaced by N;
f) a carbamoyloxy radical: xe2x80x94O(Cxe2x95x90O)N(Ry)Rz; wherein
Ry and Rz are independently selected from the group consisting of H, C1-4alkyl (optionally mono- or di-substituted by Rq, as defined previously), a three to five membered diradical to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously) and a two to five membered diradical interrupted by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously);
g) a sulfur radical: xe2x80x94(Sxe2x95x90(O)n)xe2x80x94Rs; wherein n is selected from 0, 1 or 2 and Rs is as defined previously;
h) a sulfamoyl group: xe2x80x94SO2N(Ry)Rz; wherein Ry and Rz are as defined previously;
i) an azido radical: N3;
j) a formylamino group: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)H; wherein
Rt is selected from the group consisting of H and C1-4alkyl; wherein the alkyl chain is optionally mono- or di-substituted by Rq, as defined previously;
k) a (C1-4alkyl)carbonylamino radical: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)xe2x80x94C1-4alkyl; wherein
Rt is as defined previously; wherein the alkyl chain is optionally mono-or di-substituted by Rq, as defined previously;
l) a (C1-4alkoxy)carbonylamino radical: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94C1-4alkyl; wherein
Rt is as defined previously; wherein the alkyl chain is optionally mono-substituted by Rq, as defined previously;
m) a ureido group: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)N(Ry)Rz; wherein Rt, Ry and Rz are as defined previously;
n) a sulfonamido group: xe2x80x94(Nxe2x80x94Rt)SO2Rs; wherein Rs and Rt are as defined previously;
o) a cyano group: xe2x80x94CN;
p) a (C1-4alkyl)carbonyl radical; wherein the carbonyl is acetalized: xe2x80x94C(OMe)2C1-4alkyl; wherein the alkyl is optionally mono-substituted by Rq, as defined previously;
q) a carbonyl radical: xe2x80x94(Cxe2x95x90O)Rs; wherein Rs is as defined previously;
r) a hydroximinomethyl radical; wherein the oxygen or carbon atom is optionally substituted with a C1-4alkyl group: xe2x80x94CRyxe2x95x90NORz; wherein Ry and Rz are as defined previously;
with the proviso that Ry and Rz may not be joined together to form a ring;
s) a (C1-4alkoxy)carbonyl radical: xe2x80x94(Cxe2x95x90O)OC1-4alkyl; wherein the alkyl is optionally mono- or di-substituted by Rq, as defined previously;
t) a carbamoyl radical: xe2x80x94(Cxe2x95x90O)N(Ry)Rz; wherein Ry and Rz are as defined previously;
u) a N-hydroxycarbamoyl or N(C1-4alkoxy)carbamoyl radical in which the nitrogen atom may additionally be substituted by a C1-4alkyl group: xe2x80x94(Cxe2x95x90O)xe2x80x94N(ORy)Rz; wherein Ry and Rz are as defined previously;
with the proviso that Ry and Rz may not be joined together to form a ring;
v) a thiocarbamoyl group: xe2x80x94(Cxe2x95x90S)N(Ry)Rz; wherein Ry and Rz are as defined previously;
w) a carboxyl radical: xe2x80x94COOMb; wherein Mb is as defined previously;
x) a thiocyanate radical: xe2x80x94SCN;
y) a trifluoromethylthio radical: xe2x80x94SCF3;
z) a tetrazolyl radical; wherein the point of attachment is the carbon atom of the tetrazole ring and any one nitrogen atom is mono-substituted by a substituent selected from the group consisting of hydrogen, an alkali metal and a C1-4alkyl radical; wherein the C1-4alkyl radical is optionally mono- or di-substituted by Rq, as defined previously;
aa) an anionic function selected from the group consisting of phosphono [Pxe2x95x90O(OMb)2], alkylphosphono [Pxe2x95x90O(OMb)xe2x80x94[O(C1-4alkyl)]], alkylphosphinyl [Pxe2x95x90O(OMb)xe2x80x94(C1-4alkyl)], phosphoramido [Pxe2x95x90O(OMb)N(Ry)Rz and Pxe2x95x90Oxe2x80x94(OMb)NHRx], sulfino (SO2Mb), sulfo (SO3Mb) and acylsulfonamides selected from the group consisting of CONMbSO2Rx, CONMbSO2N(Ry)Rz, SO2NMbCON(Ry)Rz and SO2NMbCN; wherein
Rx is selected from the group consisting of phenyl and heteroaryl; wherein heteroaryl is as defined previously and the phenyl and heteroaryl substituents are optionally mono- or di-substituted with Rq, as defined previously; Mb, Ry and Rz are as defined previously;
ab) a C5-C7 cycloalkyl group; wherein any one carbon atom in the ring is replaced by a heteroatom selected from the group consisting of O, S, NH and N(C1-4alkyl); and, in which any one additional carbon atom may be replaced with NH or N(C1-4alkyl) and in which at least one carbon atom adjacent to each nitrogen heteroatom has both of its attached hydrogen atoms replaced by one oxygen whereby a carbonyl moiety is formed;
with the proviso that there are at most two carbonyl moieties present in the ring;
ac) a C2-C4 alkenyl radical; wherein the radical is optionally mono-substituted by a substituent selected from the group consisting of any one of a) to ab) or is optionally mono-substituted by substituents selected from the group consisting of phenyl, pyridyl, quinoline and isoquinoline; wherein each phenyl, pyridyl, quinoline or isoquinoline substituent is optionally mono- or di-substituted by Rq, as defined previously;
ad) a C1-C4 alkyl radical;
ae) a C1-C4 alkyl mono-substituted by a substituent selected from the group consisting of any one of a) to ad);
af) a 2-oxazolidinonyl moiety; wherein the point of attachment is the nitrogen atom of the oxazolidinone ring; wherein the ring oxygen atom is optionally replaced by a heteroatom selected from the group consisting of S and NRt (wherein Rt is as defined previously) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by a substituent selected from the group consisting of any one of a) to ae);
ag) a C2-C4 alkynyl radical; wherein the radical is independently selected from the group consisting of any one of a) to af) and trialkylsilyl;
ah) phenyl radicals
ai) bicyclic radicals; wherein the radical is independently selected from the group consisting of naphthyl, biphenyl, quinoline, indolizine, indole, isoindole, indoline, benzofuran, indazole, benzimidazole, purine, quinolizine, cinnoline, quinoxaline, phthalazine and quinazoline;
aj) heterocyclic radicals; wherein the radical is independently selected from the group consisting of furyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl and isoquinolinyl; and
ak) aryl and heteroaryl radicals; wherein the radical is independently selected from the group consisting of any one of ah) through aj); wherein the radical is substituted with one to two substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxy, C1-C6 thioalkyl, halogen, cyano, hydroxy, amino, nitro and C1-C6alkylamino, in which any terminal carbon atom may be replaced by a group selected from the group consisting of carboxyl and C2-C6alkoxycarbonyl;
and pharmaceutically acceptable salts and esters thereof.
Relative to the above generic description, certain compounds of the general formula (I) are preferred. Particularly preferred embodiments are those compounds wherein:
R1 is selected from the group consisting of hydrogen, methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl, n-pentyl, cyclohexylmethyl, 3-methyl-1-butyn-3-yl, 4-dimethylaminobenzoyl, 2-hydroxymethylbenzoyl, acetyl, t-butyloxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl, 4-carbomethoxyphenoxycarbonyl, 4-methylphenoxycarbonyl, 2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl and benzyloxycarbonyl;
R2 is selected from the group consisting of hydrogen, methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl, n-pentyl, phenyl, thienyl and pyridyl;
R3 is selected from the group consisting of hydrogen, Cl, Br, F, methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl and n-pentyl; preferably, R3 is hydrogen;
R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94OCH3, xe2x80x94SCH3, -tetrazolyl, xe2x80x94COOH, xe2x80x94CH2CONH2, xe2x80x94CH2CH2SO3H, xe2x80x94CONH2, xe2x80x94SO2NH2, xe2x80x94SO3H, xe2x80x94CON(CH3)2, xe2x80x94CN, xe2x80x94CH2CN, xe2x80x94CH2SCH3, xe2x80x94CH2SO3H, xe2x80x94CH2SOCH3, xe2x80x94CH2SO2CH3, xe2x80x94SO2CH3, xe2x80x94SOCH3, xe2x80x94CH2OCH3, xe2x80x94N3, xe2x80x94OCOCNH2, xe2x80x94OH, xe2x80x94CHO, xe2x80x94CH2P(O)(OCH3)OH, xe2x80x94CF3, CH2OC(O)NH2, xe2x80x94CH2SO2NH2, xe2x80x94SCH2CH2CN, Br, Cl, F, xe2x80x94SCF3, xe2x80x94CH2SCF3, xe2x80x94SCH2CF3, xe2x80x94COCH3, xe2x80x94CHxe2x95x90NOH, xe2x80x94CONHOH, xe2x80x94C(S)NH2, xe2x80x94OCOCH3, xe2x80x94NHCOCH3, xe2x80x94NHCO2CH3, xe2x80x94NHCONH2, xe2x80x94NHSO2CH3, xe2x80x94SCN, xe2x80x94CHxe2x95x90CHCHO, xe2x80x94SCH2CH2OH, xe2x80x94CH2OH, xe2x80x94CHxe2x95x90NOCH2CO2H, xe2x80x94CO2CH2CH2OH and xe2x80x94SO2NHCH2CONH2; and
heteroaryl is selected from the group consisting of pyrrole, pyridine (1N); oxazole, thiazole, oxazine (1N+1O or 1S); thiadiazole (2N+1S); furan (1O); thiophene (1S); pyrazole, imidazole, pyrimidine, pyrazine (2N); triazole, triazine (3N); and tetrazole (4N);
and pharmaceutically acceptable salts and esters thereof.
Representative compounds of the present invention can be synthesized in accordance with the general synthetic method schemes described below and are illustrated more particularly in the specific synthetic method schemes that follow. Since the schemes are illustrations, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
Compounds of the present invention may be made in a preferred one-step reaction scheme that may be preceded or followed by various processes to obtain the desired substituents R1 to R7 and is followed by deprotection of Nxe2x80x94RPR to Nxe2x80x94R1. The preferred one-step reaction is carried out by the conventional procedure known as the Mitsunobu reaction [O. Mitsunobu, Synthesis, 1(1981)].
Referring to Scheme A, the pyridinyl alcohol Compound A1 is reacted under Mitsunobu conditions with the cyclic alkanol Compound A2 to produce the desired base ring structure of the pyridinyl ethers herein. The reaction takes place in the presence of 1 or 2 equivalents each of triphenylphosine and either diethyl- or diisopropylazodicarboxylate in a suitable solvent such as benzene, toluene or THF at room temperature to reflux overnight. Subsequently, the protecting group RPR is removed and replaced as desired. Suitable protecting groups include C1-8 substituted or unsubstituted alkyl; such as, methyl, ethyl or propyl; or C1-8 substituted acyl; such as, benzyl carboxylate, allyl carboxylate, acetyl, benzoyl or propanoyl. Many specific protecting groups RPR are included within the definition of R1. Thus, the end product may conveniently have a substitution with R1 which was utilized in the synthesis as a nitrogen protecting group. In such case, deprotection is unnecessary. 
A person skilled in the art can imagine other processes for producing compounds of Formula (I). For example, leaving groups might be employed on analogous starting material Compound A2xe2x80x2 wherein the hydroxy on Compound A2xe2x80x2 is replaced with with xe2x80x94OMs or xe2x80x94OTs and reacted with Compound A1 to form an ether linkage. The conditions for this reaction are well documented. The thioether linkage; wherein Y is S in Formula (I), can be produced in the manner employing Compound A2xe2x80x2 just described using analogous starting material Compound A1xe2x80x2, wherein hydroxy is replaced with sulfhydryl. The thioether linkage can be oxidized to S(O) or S(O)2 by the use of oxidizing agents such as the peroxides.
The terms used in describing the invention are commonly used and known to those skilled in the art.
With reference to the above definitions, the term xe2x80x9calkylxe2x80x9d refers to a straight or branched chain aliphatic hydrocarbon radical.
The term xe2x80x9cpharmaceutically acceptable salts and esters thereofxe2x80x9d refers to those salt and ester forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which would favorably affect the pharmacokinetic properties of said compounds of the present invention. Those compounds having favorable pharmacokinetic properties would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which possess such pharmacokinetic properties to provide sufficient palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of raw materials, ease of crystallization, yield, stability, hygroscopicity, and flowability of the resulting bulk drug.
Examples of suitable salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.
Examples of suitable esters include such esters wherein xe2x80x94COOMa, xe2x80x94COOMb and xe2x80x94COOH are replaced with p-methoxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, 9-anthryloxycarbonyl, CH3SCH2COOxe2x80x94, tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxycarbonyl, fur-2-uloxycarbonyl, benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl, 2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl or tetrahydropyran-2-yloxycarbonyl.
The preferred compounds of the present invention are listed in Table 1 and include compounds of the formula: 
wherein R1 to R7 and m are selected concurrently from the group consisting of:
Compounds of Formula (I) may be used in pharmaceutical compositions to treat patients (humans and other primates) with disorders related to the modulation of the nicotinic acetylcholine receptor. Thus, the compounds are effective in the treatment of pain, Alzheimer""s disease, memory loss/dementia or loss of motor function. The compounds are particularly effective in the treatment of pain.
The preferred route is oral administration, however compounds may be administered by intravenous infusion or topical administration. Oral doses range from about 0.05 mg to about 100 mg, daily. Some compounds of the invention may be orally dosed in the range from about 0.05 mg to about 50 mg daily, while others may be dosed in the range from about 0.05 mg to about 20 mg daily. Infusion doses can range from about 1.0 to about 1.0xc3x97104 mg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. For topical administration, compounds of Formula (I) may be mixed with a pharmaceutical carrier at a concentration from about 0.1% of drug to about 10% of drug to vehicle.
The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques. Oral dosage forms may be elixirs, syrups, capsules tablets and the like. Where the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known to those skilled in the art of preparing dosage forms. Parenteral dosage forms may be prepared using water or another sterile carrier.
In order to illustrate the invention the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those skilled in the art may find other methods of practicing the invention, which are obvious to them. However those methods are deemed to be within the scope of this invention.
Reagents were purchased from Aldrich, Lancaster, Pfaltz and Bauer, TCI America, and used without further purification. 1H NMR spectra were collected on a Bruker AC-300 spectrometer. Chemical shifts are reported with respect to tetramethylsilane (TMS) xcex4H,C=0.0 ppm. Spectra were acquired at ambient temperature using DMSO-d6, CD3OD or CDCl3. Mass spectral analyses were performed on a Fisons instrument (Hewlett-Packard HPLC driven electrospray MS instrument). Analytical HPLC analyses were performed on a Hewlett-Packard liquid chromatography system (YMC column, 4 mmxc3x9750 mm, 4 mm C18, 1.0 mL/min, 8 min gradient from 95% aqueous media (0.1% TFA) to 95% CH3CN (0.1% TFA), 220 and 260 nm).